For the understanding of the invention, first the following technological background is important. The activation of resting T cells for the proliferation and functional differentiation first requires the occupation of two surface structures, so-called receptors: i.e. of the antigen receptor having a different specificity from cell to cell and being necessary for the detection of antigens, for instance viral fission products; and of the CD28 molecule expressed in an identical manner on all resting T cells with the exception of one sub-group of the human CD8 T cells, said CD28 molecule binding in to ligands on the surface of other cells. This is called the costimulation of the antigen-specific immune reaction by CD28. In cell culture, these processes can be simulated by occupying the antigen receptor and the CD28 molecule by suitable mAbs. In the classical system of the costimulation, neither the occupation of the antigen receptor nor of the CD28 molecule alone will lead to the T cell proliferation, the occupation of both receptors is however effective. This observation has been made for T cells of man, mouse and rat.
There are known, however, also mAbs that can alone initiate the T cell proliferation. Such a superagonistic (that is independent from the occupation of the antigen receptor) activation of resting T cells has been observed in the following systems: in the document Brinkmann et al., J. Immunology, 1996, 156: 4100-4106, it has been shown that a very small fraction (5%) of human T lymphocytes carrying the surface marker CD45 RO being typical for resting T lymphocytes, is activated by the CD28-specific mAb 9.3 normally requiring costimulation with addition of the growth factor interleukin-2 (IL-2) without occupation of the antigen receptor. In the document of Siefken et al., Cellular Immunology, 1997, 176: 59-65, it has been shown that a CD28-specific mAb produced in a conventional manner, i.e. by immunization of mice with human cells, can activate in cell culture a sub-group of human T cells without occupation of the antigen receptor for the proliferation, if CD28 is occupied by this mAb and the cell-bound mAbs are in addition cross-linked with each other by further antibodies. It is common to the in this respect known antibodies that only a small fraction of the T cells can be activated.
In the document of Tacke et al., Eur. J. Immulog., 1997, 17: 239-247, two kinds of CD28-specific monoclonal antibodies with different functional properties have been described: costimulatory mAbs costimulating the activation of resting T cells with a simultaneous occupation of the antigen receptor only; and superagonistic mAbs being able to activate T lymphocytes of all classes in vitro and in animal experients for the proliferation, without occupation of the antigen receptor. Both in this respect known mAbs originate from an immunization with cells, on the surface of which rat CD28 is expressed, and which are obtainable by different selections directed to their respective properties. Finally, from WO 98/54225 is known another superagonistic mAb, namely CMY-2.
The in this respect known superagonistic mAbs do not meet in their stimulatory effect the requirements with regard to the strength of the activating effect or the width of the activated sub-populations of T lymphocytes or do not have the required human specificity.